Amides of isoindoline-2-carboxylic acid



United States Patent 3,535,323 AMIDES 0F ISOINDOLINE-Z-CARBOXYLIC ACID Karl-Heinz Heidenbluth, Radebeul, Reingard Schefiler, Dresden, Joachim Schmidt, Magdeburg, and Heinz Tonjes, Radebeul, Germany, assignors to VEB Arzneimittelwerk Dresden, Dresden-Radebeul, Germany No Drawing. Continuation-impart of application Ser. No.

447,117, Apr. 8, 1965. This application Apr. 4, 1968, Ser. No. 718,935

Int. Cl. C07d 27/48 U.S. Cl. 260-294 15 Claims ABSTRACT OF THE DISCLOSURE Compounds having a high order of analgesic and sedative properties of the formula in which Y stands for hydrogen, a nitro group or an amino group, and R and R are each of the group consisting of hydrogen, lower alkyl, alkenyl to C lower hydroxyalkyl, cycloalkyl or aryl radicals, and R together with R and the N of the amino group may form a 5-to 6-membered ring.

This application is a continuation-in-part of our copending application Ser. No. 447,117, filed Apr. 8, 1965, now abandoned.

This invention relates to novel amides of iso-indoline- 2-carboxylic acid and more particularly pertains to amides of iso-indoline-Z-carboxylic acid which can be obtained by ordinary industrial methods and which show a high order of analgesic and sedative properties over an extended period of time. These compounds are described by a general formula in which Y stands for hydrogen, a nitro group or an amino group, and R and R are each of the group consisting of hydrogen, lower alkyl, alkenyl to C lower hydroxyalkyl, cycloalkyl, or aryl radicals and R together With R and the N of the amino group may form a 5-to-6- membered ring.

From this series, only the simple amide of isoindoline-Z- carboxylic acid has been known up to date. This simple amide of iso-indoline-2-carboxylic acid was obtained by reacting cyanogen bromide with N-allyl-iso-indoline with subsequent saponification of the resulting iso-indo1ine-2- carboxylic acid nitrile; the yield of the first stage was 40% of the theoretical; the yield of the second stage is not mentioned.

The new compounds of this invention are obtained by reacting an iso-indoline of the general formula in which Y represents a hydrogen atom or a nitro group, with isocyanates, carbamic acid chlorides, reactive urea derivatives or phosgene in a manner known per se. In the case in which iso-indoline-Z-carboXylic acid chloride is obtained it is subjected to aminolysis. In the case when Y represents a nitro group, the aromatic nitro group may be reduced to an amino group. The amide is thus easily obtainable in one stage, and it has been found that by using this process a greatly increased yield was obtained as compared to the only 40% of the theoretical yield for the first stage previously obtained. When Y=H and both R and R =H, up to 74% of the theoretical yield has been obtained.

It is accordingly an object of this invention to provide new amides of iso-indoline-2-carboxylic acid of the general formula in which Y represents a hydrogen atom or a nitro group, with isocyanates, carbamic acid chlorides, reactive urea derivatives or phosgene in a known manner and in the cases where iso-indoline-2-carboxylic acid chlorides are obtained subjecting them to subsequent aminolysis. It is a further object of this invention to obtain iso-indoline-2- carboxylic acid amides with specially good analgesic and sedative properties .over an extended length of time.

It should be noted that R and R which are mentioned to consist of lower alkyl or lower hydroxyalkyl preferably stand for alkyls of the chain-length C to C In many cases Y stands for hydrogen; R and/or R may also be hydrogen. As regards the aryl radical, the preferred radicals are phenyl and benzyl.

In order that the compounds of this invention be readily appreciated by and fully available to those skilled in the art, the following illustrative but not limiting examples of the preparations thereof are supplied.

EXAMPLE 1 To a solution of 5 g. iso-indoline in ccs. of dry acetone a solution of 5 g. phenyl isocyanate in 30 cos. acetone is added dropwise, while stirring over a period of fifteen minutes. The solution is left overnight; the mother liquor is filtered off and concentrated in vacuo. The resulting crystallisate of iso-indoline-Z-carboxylic acid anilide is recrystallized from ethanol. Yield: 3.5 g.=35% of the theoretical yield; melting point 187-188 C. C15H14N2O N 1 =11.75%, N =11.59.

EXAMPLE 2 g. of S-nitroisoindoline are reacted with 1.7 g. methyl-iso-cyanate, as described in Example 1; Yield: 4 g. 5- nitro-iso-indoline-Z-carboxylic acid methylamide=60% of the theoretical yield; melting point undefined; decomposition from 260 C. C H N O (221.21): N =19.0%, N =19.17%.

From this, 2.3 g. 5-amino-iso-indoline-2-carboxylic acid methylamide are obtained by catalytic hydrogenation with PdO as actalyst in ethanol under normal conditions. Yield: 60.5% of the theoretical yield; melting point 199202 C., elimination of water at 97 C. to 100 C. C H N O.H 0 (209.25): N =20.08%, N,.,,,,,,,: 19.79

EXAMPLE 3 8.5 g. iso-indoline are reacted with 9.3 benzyl isocyanate as described in Example 1. Yield: 7 g. iso-indoline- Z-carboxylic acid benzylamide which represents 39% of hte theoretical yield; melting point 137 C. (ethanol). C H N O (252.16): N =11.l1%, N,-., =l0.96%.

EXAMPLE 4 6.78 g. of 5-nitro isO-indoline are reacted with 5.1 g. cyclohexyl isocyanate as described in Example 1. Yield: 6.4 g. 5-nitro iso-indoline-Z-carboxylic acid cyclohexylamide which represents 53.8% of the theoretical yield; melting point 141 C. (ethanol). CH19N303 N =14.51%, N; =14.30%.

The hydrochloride of S-amino-iso-indoline-2-carboxylic acid cyclohexylamide is obtained by catalytic hydrogenation. Melting point 207-209 C. (ethanol/ether). C15H22C1N30 I N m) Nf f= 14.10%.

EXAMPLE 5 To a mixture of 4 g. iso-indoline, 4 ccs. triethylamine and 50 ccs. chloroform, a solution of 3.6 g. dimethyl carbamic acid chloride in 20 ccs. chloroform is added dropwise, while stirring, at room temperature. The mixture is subsequently refluxed for five hours. After distilling off the solvent in vacuo, the residue is shaken with 50 ccs. diluted HCl; the iso-indoline-Z-carboxylic acid dimethylamide separated is drawn off and recrystallized from water. Yield: 3.5 g.=56% of the theoretical yield, melting point 130 C. C H N O (190.24): N 14.72%, N =14.49%.

EXAMPLE 6 To a mixture of 4.75 g. 5-nitro iso-indoline, 2.3 pyridine, and 50 ccs. chloroform, a solution of 6.57 g. diphenyl carbamic acid chloride in 50 ccs. chloroform is added dropwise, while stirring, at room temperature. The mixture is subsequently heated to 5070 C. for five hours. The cooled reaction mixture is extracted with 100 ccs. 0.5 N HCl in three portions, washed with water and the dried chloroform phase freed from the solvent in vacuo. The solid residue of crude 5-nitro-iso-indoline-2- carboxylic acid diphenylamide is recrystallized from ethanol. Yield: 7.5 g.=73% of the theoretical yield. Melting point 160.5161.5 C. C21H1qN3O3 (359.37): ea1e. found 3.75 g. of hydrochloride of 5-amino-iso-indoline-2- 4 carboxylic acid diphenylamide are obtained by catalytic hydrogenation. Yield: 54.4% of the theoretical yield. Melting point 21 C. (ethanol/ether). C H C1N O (365.85): N =11.49%, N =11.52%.

EXAMPLE 7 5.95 g. iso-indoline are mixed by stirring in 60 ccs. water, and 5.25 g. nitro urea are introduced by portions. The crystals which are separated after approximately ten minutes, are drawn olf, heated to melting point over a short period to remove the N 0 formed during the reaction and then recrystallized from water. Yield 6 g. isoindoline-Z-carboxylic acid amide which represents 74% of the theoretical yield; melting point 185186 C. C H N O (162.19): N =17.27%, N =17.19%.

EXAMPLE 8 4.1 g. 5-nitro-iso-ind01ine are reacted with 3.2 g. nitro urea as described in Example 5. Yield: 3.7 g. 5-nitro-isoindoline-Z-carboxylic acid amide=72% of the theoretical yield; melting point 193-194 C. (water). C H N O (207.19): N =20.28%, N =20.13%.

From this, 2.7 g. 5-amino-iso-indoline-2-carboxylic acid amide are obtained by catalytical hydrogenation; Yield: 87% of the theoretical yield; melting point 201-202 C. (ethanol). C H N O (177.20); N =23.72%, N =23.73%.

EXAMPLE 9 T o a solution of iso-indoline in toluene, an excess of phosgene is introduced, while stirring, at room temperature. The solution is subsequently heated to 90 C. for one to two hours. After cooling, the insoluble matter is filtered oil, the filtrate is concentrated in vacuo, and the residue is recrystallized from benzene/petroleum ether. The iso-indoline-2-carboxylic acid chloride obtained having a melting point of 125-127 C., is reacted as follows: To a mixture of 1.6 g. piperidine, 2 g. triethylamine and 30 cos. acetone, a solution of 3.5 g. isoind0line-2-carboxylic acid chloride in 140 ccs. acetone is added dropwise, while stirring. The mixture is subsequently refluxed for one hour. After cooling, the triethylamine hydrochloride is drawn off, mixed with 35 ccs. of diluted HCl, and the major portion of acetone distilled off in vacuo. During cooling, 4.1 g. iso-indoline-Z-carboxylic acid piperidide crystallized from the remaining solution, which represents 93% of the theoretical yield. Melting point 7071 C. (acetone). C H N O (230.30); N =12.16%, N =ll.94%.

EXAMPLE 10 To a mixture of 4.52 g. diethylamine, 6.26 g. triethylamine, and 50 ccs. acetone, a solution of 14.0 g. S-nitroiso-indoline-2-carboxylic acid chloride (having a melting point of C.), made as described in Example 9, in ccs. acetone is added dropwise, while stirring, at room temperature over a period of twenty minutes. The mixture is subsequently heated to boiling for two hours. After cooling, triethylamine hydrochloride is drawn off; the filtrate is mixed with 50 ccs. of diluted HCl, and the major portion of the solvent is distilled off in vacuo. From the remaining solution, crude S-nitro-iso-indoline-2-carboxylic acid diethylamide crystallizes, which is recrystallized with ethanol for purification, and Washed with 300 ccs. water on the frit. Yield: 13.6 g.=83.7% of the theoretical yield; melting point 90-91 C. (benzene/ether). C H N O (263.29): N =15.96%, N =l5.60%.

From this, the hydrochloride of S-amino iso-indoline- 2-carboxylic acid diethylamide is obtained by catalytic hydrogenation. Melting point (not clearly defined) from 178188 C. (ethanol/ether). C H ClN O (269.77): N =15.57%, N =15.24%.

Further examples are contained in tabulated form in the following table:

TABLE 1 N-determination cal./ Y R1 R2 Boiling point, C. (solvent) Formula rnol (weight) found Example No.:

11 H H CH; 210 (Ethanol)-.- CH12N2O (176.20) 15.89/15. 68 H -C;H 223 (Ethanol)- C11H14N20 (190.24) 14. 72/14. 66 --H iC3H7 129-130 (Ethanol CmHmNaO (204.17) 13. 72/13. 76 H -iC4H9 82 Petroleum ethe GrsHmNgo (218.28) 12. 82/13. 14 H -CHz-CH= CH2 198-199 (Ethanol) cflHflNflo (202.24) 13. 85/13. 72 -H -CHzCH -OH 5-186 C H N O2 (206.24) 13. 58/13. 55 -iC4Hg i-C H 115-116 (Ethanol). CnHggNzO (320.46) 8. 75/8. 68 CflH5 C5H5 173 (Ethanol) C21H13N2O (314.37) 8. 91/8. 93 7 19 H H 108-109 (Acetone) CnHmNzO (216.27) 12. 95/12. 69

20 H R 137-138 (Acetone) o13HmN202 (232.27) 12. 06/11. 78

21 H 113 (Acetic acid ester) C15H20N2O (244.32) 11. 46/11. 37

22 NO2 -H -C 2H5 243-244 (Ethanol) C11H13N303 (235.24) 17. 86/17. 68 NH: -H -CH5 60-62 (Water) CuHrsNaO (205.25) 20. 48/20. 16

23 -NO2 H -CH2CH=CH1 225-226 (Ethanol) O H N O (247.25) 16.99/16. 81 NH; --H --CHz-CH=CH2 128-129 (Propanol petroleum ether) C H N O (217.26) 19. 30/19. 36

24. 'NO2 -H 1CaH1 186-187 (Acetic 9.0111 ester) CrzHrsNaOa (249.48) 16. 84/16. 84 -NH2 H 1C3H1 193-194 (Ethanol ether) CuHrsClNaO (255.83) 16. 42/16. 15 25 NO -H C6H5 211-212 (Ethanol)- C15H1 N O (283.28) 14. 84/14. 96 NHg H -CgH 166-167 (Ethanol) O H15N3O (253.29) 16. 59/16. 69

26 NO:| H OH2OQH5 168-170 (Ethanol) CwHwNgO; (297. 14. 14/14. 31 NH; --H -CHg-C5H5 71-72 (Ethanol) CwNggNaO (313.39) 13. 41/13. 60+

27 -NO: -CH3 CH2-C5H5 159 Water CnHraNaOa (235.24) 17. 86/17. 60 NH: -GH -CH 209-211 (Ethanol) CuHmclNao (241.72) 17. 39/17. 23

28 -NO H 158-159 (Ethanol) C H N 0 (261.27) 16. 08/16. 12

-NH; H 147-148 (Ethanol) C13H17N3O (231.29) 18. 17/18.

29 -NH2 H 131-132 (Benzene petroleum ether)- CHHI N O (245.31)- 17. 15/117. 13

-N01 H 129-130 (Ethanol)- C1 H1 N O (275.27)- 15. 26/15. 36

30 -NO2 H -iC4Ha 184-185 (Ethanol) O1 H N O (263.29) 15. 96/15. 93 1 -H iO4H 225 (Ethanol ether) 0131120011630 (269.77) 15. 65/15. 66

*Oompounds 17 and 26 crystallize with 1 M01 ethanol.

In the following table, a number of pharmaceutical data are listed for the purpose of illustrating the efiectiveness of some of the new products as compared to known a member selected from the group consisting of H, lower alkyl, allyl, hydroxy-lower alkyl, cyclohexyl and phenyl, and when taken together with the adjacent N atom a memdrugs. The data were collected in tests carried out on mice. her selected from the group consisting of pyrrolidino,

TABLE 2 Antl- Analgesic efiect pyreticl efiect in Tall ieverlng Antiphlogistic effect; Electric irritation 1rats; lower LD, mg./kg.

ower LDsu, E1350, LD,,i Dextran- Formalin mgJkg. mgJkg. LDwzEDso mg./kg. edema edema Iso-lnd01lne-2-earboxylle acid amide 620 50 12. 4 10 20 20 Iso-indoline-2carboxylic acid methylamide 360 45 8. 0 10 10 50 lso-lndollne-ircarboxyllc acid dlmethylamide. 410 7. 5 10 20 20 Amino henazone 320 2.7 20 100 100 Phony utazonesodium 260 1.8 50 150 What is claimed is: piperidino and morpholino, with the proviso that Y, R 1. A compound of the formula and R are not simultaneously hydrogen.

CH2 2. The compound as claimed in claim 1, wherein Y Y 7 stands for hydrogen, R is hydrogen and R is phenyl. NC O-N 3. The compound as claimed in claim 1, wherein Y stands for NH R is hydrogen and R is methyl.

CH2 4. The compound as claimed in claim 1, wherein Y wherein Y is a member selected from the group consisting of hydrogen, nitro, and amino, and R and R are each 75 stands for hydrogen, R is hydrogen and R is benzyl. 5. The compound as claimed in claim 1, wherein Y 8. The compound as claimed in claim 1, wherein Y 5 is N0 R and R are phenyl.

9. The compound as claimed in claim 1, wherein Y is N0 R and R each are hydrogen.

10. The compound as claimed in claim 1, wherein Y 10 is NH R and R each are hydrogen.

11. The compound as claimed in claim 1, wherein Y stands for hydrogen, R and R together with the N of the amino-group is piperidino.

12. The compound as claimed in claim 1, wherein Y 15 stands for NH R and R each are ethyl.

13. The compound as claimed in claim 1, wherein Y stands for N0 R is hydrogen and R is methyl.

14. The compound as claimed in claim 1, wherein Y stands for NH R and R are phenyl.

15. The compound as claimed in claim 1, wherein Y stands for N0 R and R each are ethyl.

References Cited UNITED STATES PATENTS 3,285,908 11/1966 Shen 260-211 3,308,130 3/1967 Bousquet 260294 FOREIGN PATENTS 3,661 12/1965 France.

OTHER REFERENCES Neumeyer: J. Pharm. Sci., 53 (8), 981-2 (1964).

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R. 

